RESUMEN
We synthesized the novel seco cyclopropa[c]pyrrolo[3,2-e]indole (CPI) bisalkylators and evaluated their antitumor activity. Among these derivatives, 11a (AT-760), in which the two seco 3-methoxycarbonyl-2-trifluoromethyl CPI (MCTFCPI) moieties are connected with a 3,3'-(1,4-phenylene)bisacryloyl group, was found to exhibit more potent cytotoxicity and antitumor activity against HeLaS3 human uterine cervix carcinoma cells and Colon 26 adenocarcinoma cells, respectively, than 8 (bizelesin, U-77,779). It also appeared that compound 11a exhibits improved in vivo efficacy in the human colon CX-1 model when compared to either compound 8 or mitomycin C (MMC). Efficacious doses for 11a were found to be 2-fold lower than those for 8.
Asunto(s)
Antineoplásicos Alquilantes/síntesis química , Compuestos de Bencilideno/síntesis química , Pirroles/síntesis química , Urea/análogos & derivados , Animales , Antineoplásicos Alquilantes/química , Antineoplásicos Alquilantes/farmacología , Compuestos de Bencilideno/química , Compuestos de Bencilideno/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Duocarmicinas , Humanos , Indoles/farmacología , Concentración 50 Inhibidora , Ratones , Ratones Desnudos , Pirroles/química , Pirroles/farmacología , Relación Estructura-Actividad , Trasplante Heterólogo , Células Tumorales Cultivadas , Urea/farmacologíaRESUMEN
Two angiotensin-I-converting enzyme (ACE) inhibitory peptides were isolated from a tryptic hydrolysate of human serum albumin (HSA). The peptides were identified by sequencing and other analyses as Ala-Trp and the nonapeptide Ala-Phe-Lys-Ala-Trp-Ala-Val-Ala-Arg (human albutensin A), corresponding to f(213-214) and f(210--218) of HSA, respectively. Synthetic versions of both peptides had previously been shown to have ACE inhibitory activity. The present results are the first to show that these peptides have a potential natural origin in humans. Additional studies were done to define the inhibitory properties of these peptides, as they had not been previously reported. The dipeptide and nonapeptide showed dose-dependent inhibition of ACE, with IC50 values of 12 and 1.7 micromol/l, respectively. Lineweaver-Burk plots suggested that Ala-Trp is a competitive inhibitor, and that human albutensin A is a noncompetitive inhibitor.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Oligopéptidos/farmacología , Albúmina Sérica/farmacología , Tripsina/metabolismo , Corteza Suprarrenal/metabolismo , Aldosterona/metabolismo , Inhibidores de la Enzima Convertidora de Angiotensina/aislamiento & purificación , Bradiquinina/metabolismo , Cromatografía Líquida de Alta Presión , Dipéptidos/aislamiento & purificación , Dipéptidos/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Hidrólisis , Oligopéptidos/aislamiento & purificación , Peptidil-Dipeptidasa A/metabolismo , Peptidil-Dipeptidasa A/fisiología , Albúmina Sérica/aislamiento & purificación , Albúmina Sérica/metabolismoRESUMEN
A series of novel nikkomycin analogue inhibitors of the chitin synthase of fungal cell wall was synthesized and evaluated for their inhibitory activities. Among them, the compound having a phenanthrene group at the terminal amino acid was found to possess strong anti-chitin synthase activity.
Asunto(s)
Aminoglicósidos , Antibacterianos/química , Antibacterianos/farmacología , Quitina Sintasa/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Sustitución de Aminoácidos , Antibacterianos/síntesis química , Antibacterianos/metabolismo , Sitios de Unión , Candida/enzimología , Pared Celular/enzimología , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Estructura Molecular , Conformación ProteicaRESUMEN
We previously described a novel angiotensin-I-converting enzyme (ACE) inhibitory peptide, designated Acein-1, that was isolated from a tryptic hydrolysate of human plasma. We now report a second such inhibitory peptide, Acein-2 obtained from the same hydrolysate. The peptide was purified by gel filtration and cation exchange chromatography followed by reversed-phase gradient and isocratic high performance liquid chromatography. Acein-2 was found to be a tripeptide, Leu-Ile-Tyr, which is thought to correspond to f(518-520) of human alpha2-macroglobulin. The synthetic tripeptide showed a potent dose-dependent inhibition of ACE, with an IC(50) value of 0.82 micromol/l. Lineweaver-Burk plots suggested that Acein-2 as well as the previously described Acein-1 are non-competitive inhibitors.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/aislamiento & purificación , Fragmentos de Péptidos/aislamiento & purificación , Plasma/química , Albúmina Sérica/aislamiento & purificación , Antihipertensivos/aislamiento & purificación , Fraccionamiento Químico , Cromatografía en Gel , Cromatografía Líquida de Alta Presión , Cromatografía por Intercambio Iónico , Humanos , Cinética , Fragmentos de Péptidos/química , Albúmina Sérica/química , Albúmina Sérica Humana , Tripsina , alfa-Macroglobulinas/químicaRESUMEN
The bactericidal activity of gatifloxacin, a new 6-fluoro-8-methoxy quinolone, was determined in a dynamic in vitro model mimicking complicated lower urinary tract infection. Strains of Pseudomonas aeruginosa and Enterococcus faecalis with different susceptibility were exposed to changing gatifloxacin concentrations, simulating human urinary concentrations afer oral treatment with 200 mg twice daily for 3 consecutive days. Bacterial numbers of P. aeruginosa (minimal inhibitory concentrations, MIC: < or =32 microg/ml) and of E. faecalis (MIC: 16 microg/ml) were reduced to undetectable levels during exposure. For the strains with lower susceptibility, gatifloxacin showed bactericidal activity, but eradication was not complete. Thus, in a complicated urinary tract infection model, breakpoint MICs of gatifloxacin for uropathogenic organisms were presumed to range from 16 to 32 microg/ml. At least 86% of recent clinical isolates of P. aeruginosa and E. faecalis were inhibited at its breakpoint MIC. These results suggest that gatifloxacin may be useful in the treatment of urinary tract infections.
Asunto(s)
Antiinfecciosos/administración & dosificación , Antiinfecciosos/orina , Enterococcus faecalis/efectos de los fármacos , Fluoroquinolonas , Modelos Biológicos , Pseudomonas aeruginosa/efectos de los fármacos , Vejiga Urinaria/efectos de los fármacos , Vejiga Urinaria/microbiología , Administración Oral , Antiinfecciosos/farmacocinética , Gatifloxacina , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Infecciones por Bacterias Grampositivas/orina , Humanos , Infecciones por Pseudomonas/tratamiento farmacológico , Infecciones por Pseudomonas/orina , Factores de Tiempo , Vejiga Urinaria/metabolismo , Enfermedades de la Vejiga Urinaria/tratamiento farmacológico , Enfermedades de la Vejiga Urinaria/orina , Infecciones Urinarias/tratamiento farmacológico , Infecciones Urinarias/orinaRESUMEN
GA0113 is a newly developed angiotensin II (Ang II) AT1-receptor antagonist having a quinoline moiety. This study was undertaken to clarify the pharmacologic profile of GA0113. In vitro profiles of GA0113 for Ang II receptors were examined in a receptor-binding assay and an Ang II-induced vasoconstriction study. Antihypertensive effects after single or repeated oral administrations were examined in conscious renal hypertensive (RH) or spontaneous hypertensive (SH) rats. Blood pressure (BP) and heart rate were measured by the tail-cuff method. GA0113 interacted with AT1 receptors in a competitive manner, but showed an insurmountable antagonistic action in Ang II-induced vasoconstriction. In RH rats, GA0113 (0.01-1 mg/kg) reduced BP with ED25 values of 0.015 mg/kg, and required 0.1 mg/kg for 24-h BP control. Repeated administration of GA0113 in SH rats (0.03-0.1 mg/kg) showed moderate onset and gradually potentiated reduction of BP, which reached a plateau after day 4 of treatment without alteration in heart rate. There was no tolerance of the hypotensive action or rebound phenomenon after cessation of the treatment. In pharmacokinetic studies, GA0113 shows excellent oral bioavailability (94%) and a long circulating half-life (12 h) in rats. These findings indicate that GA013 may serve as a highly potent and effective antihypertensive agent in humans. GA0113, with its unique chemical structure and pharmacologic and pharmacokinetic profiles may provide new possibilities in hypertension therapy.
Asunto(s)
Antagonistas de Receptores de Angiotensina , Presión Sanguínea/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Quinolinas/farmacología , Sulfonamidas/farmacología , Animales , Unión Competitiva , Disponibilidad Biológica , Relación Dosis-Respuesta a Droga , Técnicas In Vitro , Masculino , Unión Proteica , Quinolinas/farmacocinética , Conejos , Ensayo de Unión Radioligante , Ratas , Ratas Endogámicas SHR , Ratas Wistar , Receptor de Angiotensina Tipo 1 , Receptor de Angiotensina Tipo 2 , Sulfonamidas/farmacocinética , Factores de Tiempo , Vasoconstrictores/farmacologíaRESUMEN
The seco-Cl 3-methoxycarbonyl-2-trifluoromethylcyclopropapyrroloindole (MCTFCPI) derivatives dl- and/or (S)-10 carrying various acyl moieties at the N6-position were synthesized along with their prodrugs (S)-12, and their antitumor activity was evaluated. Among these derivatives, AT-3510 [(S)-12m], the novel prodrug MCTFCPI derivative carrying a 5-(7-methoxybenzofuran-2-ylcarbonyl)aminoindole-2-carb onyl group at the N6-position, was found to exhibit more excellent antitumor activity against human tumor xenografts than the clinical trial candidates carzelesin (6) and KW-2189 (7) and cisplatin.
Asunto(s)
Antineoplásicos/síntesis química , Benzofuranos/síntesis química , Profármacos/síntesis química , Pirroles/síntesis química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Benzofuranos/química , Benzofuranos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Profármacos/química , Profármacos/farmacología , Pirroles/química , Pirroles/farmacología , Estereoisomerismo , Relación Estructura-Actividad , Trasplante Heterólogo , Células Tumorales CultivadasRESUMEN
A series of novel nikkomycin analogs, which inhibited chitin synthase, the fungal cell wall biosynthesis enzyme, has been synthesized and evaluated their inhibitory activities.
Asunto(s)
Aminoglicósidos , Antibacterianos/química , Antibacterianos/síntesis química , Antifúngicos/síntesis química , Quitina Sintasa/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Antibacterianos/farmacología , Antifúngicos/química , Antifúngicos/farmacología , Diseño de Fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Modelos Moleculares , Relación Estructura-Actividad , Uridina Difosfato N-Acetilglucosamina/químicaRESUMEN
A novel angiotensin-I-converting enzyme (ACE) inhibitory peptide, designated acein-1, was isolated from the tryptic hydrolysate of human plasma. Gel filtration and cation exchange chromatography were performed to purify this peptide, followed by reversed-phase gradient and isocratic high-performance liquid chromatography. Acein-1 was found to be a heptapeptide, Tyr-Leu-Tyr-Glu-Ile-Ala-Arg, corresponding to f(138-144) of human serum albumin. The synthetic heptapeptide, hexapeptide (Tyr-Leu-Tyr-Glu-Ile-Ala, des-7R acein-1) and octapeptide (Tyr-Leu-Tyr-Glu-Ile-Ala-Arg-Arg, acein-1R) showed dose-dependent inhibitions of ACE, and their IC50 values were 16 micromol/l, 500 micromol/l and 86 micromol/l, respectively. Acein-1 might be a non-competitive inhibitor, while acein-1R may be an uncompetitive inhibitor, as shown by Lineweaver-Burk plots.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/química , Fragmentos de Péptidos/química , Albúmina Sérica/química , Secuencia de Aminoácidos , Inhibidores de la Enzima Convertidora de Angiotensina/sangre , Inhibidores de la Enzima Convertidora de Angiotensina/aislamiento & purificación , Cromatografía en Gel , Cromatografía por Intercambio Iónico , Humanos , Hidrólisis , Cinética , Espectrometría de Masas , Fragmentos de Péptidos/aislamiento & purificación , Peptidil-Dipeptidasa A/metabolismo , Albúmina Sérica/aislamiento & purificación , Albúmina Sérica/fisiología , Albúmina Sérica Humana , TripsinaRESUMEN
The novel 3-methoxycarbonyl-2-trifluoromethylcyclopropapyrroloindole (MCTFCPI) bisalkylators were synthesized and their antitumor activity was evaluated. Among these derivatives, 7f in which two MCTFCPI moieties are connected with a 5,5'-bis(2-carbonyl-1H-indole) group, was found to exhibit more prominent cytotoxicity and antitumor activity than U-77,779 (bizelesin) (2).
Asunto(s)
Antineoplásicos Alquilantes/síntesis química , Indoles/síntesis química , Pirroles/síntesis química , Animales , Antineoplásicos Alquilantes/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Duocarmicinas , Células HeLa , Humanos , Indoles/farmacología , Concentración 50 Inhibidora , Ratones , Pirroles/farmacología , Relación Estructura-Actividad , Células Tumorales Cultivadas , Urea/análogos & derivados , Urea/farmacologíaRESUMEN
The novel cyclopropapyrroloindole(CPI) bisalkylators were synthesized and their antitumor activity was evaluated. Among these derivatives, AT-760 (5a) in which the two 3-methoxycarbonyl-2-trifluoromethylCPI (MCTFCPI) moieties are connected with a 3,3'-(1,4-phenylene)diacryloyl group, was found to exhibit more prominent cytotoxicity and antitumor activity than U-77,779 (bizelesin) (1).
Asunto(s)
Antineoplásicos Alquilantes/química , Compuestos de Bencilideno/química , Pirroles/química , Adenocarcinoma/patología , Animales , Antineoplásicos Alquilantes/síntesis química , Antineoplásicos Alquilantes/farmacología , Compuestos de Bencilideno/síntesis química , Compuestos de Bencilideno/farmacología , División Celular/efectos de los fármacos , Neoplasias del Colon/patología , Células HeLa , Humanos , Ratones , Pirroles/síntesis química , Pirroles/farmacología , Relación Estructura-ActividadRESUMEN
The antihypertensive effects of oral or intravenous administration of AE0047, a novel 1,4-dihydropyridine-type calcium antagonist, were investigated in spontaneously hypertensive rats (SHR/crj), one kidney-one clip renal hypertensive rats (RHR), deoxycorticosterone acetate (DOCA)-salt hypertensive rats (DHR) and two kidney-one clip renal hypertensive dogs (RHD). AE0047 (1, 3, 10 mg/kg, p.o.) caused a dose-related reduction of systolic blood pressure (SBP) with low reflex tachycardia in SHR/crj and RHR. The effect reached its maximum at 2-4 hr after administration and was sustained for a long time. In DHR, AE0047 (0.3, 1, 3 mg/kg, p.o.) similarly showed the antihypertensive effects at 2-7 hr with no significant changes in heart rates (HR). The doses (ED30) of AE0047 required to decrease SBP by 30% were 2.6, 3.4 and 0.68 mg/kg in SHR/crj, RHR and DHR, respectively. In RHD, and AE0047 capsule (GJ-0956: 4, 8, 16, 32 mg/body, p.o.) produced dose-dependent and long lasting effects with a transient and slight increase in HR. Furthermore, the intravenous administration of AE0047 (10, 30, 100 micrograms/kg) produced the antihypertensive action slowly, reached a plateau 10 min later and then maintained for many hours. In contrast, nitrendipine (3-100 mg/kg, p.o., 3-30 micrograms/kg, i.v.) and nicardipine (1-30 mg/kg, p.o., 3-30 micrograms/kg, i.v.) exhibited a similar potency to AE0047, but these maximal effects were produced at 1-2 hr and 0.5-1 min in the case of oral and intravenous administration, respectively, with a rapid recovery in the above hypertensive rats. These results indicate that AE0047 exhibits an antihypertensive effect with a slow onset and long-lasting profile.
Asunto(s)
Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Bloqueadores de los Canales de Calcio/farmacología , Dihidropiridinas/farmacología , Hipertensión/fisiopatología , Administración Oral , Animales , Desoxicorticosterona , Perros , Relación Dosis-Respuesta a Droga , Frecuencia Cardíaca/efectos de los fármacos , Hipertensión/inducido químicamente , Hipertensión Renal/fisiopatología , Inyecciones Intravenosas , Nicardipino/farmacología , Nitrendipino/farmacología , Ratas , Ratas Endogámicas SHRRESUMEN
The antihypertensive effects of AE0047, a novel 1,4-dihydropyridine-type calcium antagonist, were investigated in spontaneously hypertensive rats (SHR/crj) and two kidney-one clip renal hypertensive dogs (RHD). AE0047, which was orally administered at the dose of 0.3, 1 or 3 mg/kg once daily for 8 consecutive weeks to SHR/crj, exhibited a dose-related decrease in systolic blood pressure. The antihypertensive action was reinforced during the drug treatment at 0.3 and 1 mg/kg. At each dose, the trough-to-peak (T/P) ratio was above 0.50 two weeks later. Although the reflex tachycardia was observed at 1 or 3 mg/kg on the 1st day, it gradually weakened within 8 weeks. Long-term treatment with AE0047 led to the regression of left ventricular hypertrophy. Furthermore, AE0047 had no influences on lipid and glucose metabolism. In RHD, and AE0047 capsule (GJ-0956) containing 2 or 8 mg of the drug was administered for 2 weeks. GJ-0956 produced no reduction in blood pressure at 2 mg, but enhanced the antihypertensive effect starting at 8 mg. The T/P ratios were 0.52 and 0.67 for the systolic and diastolic pressure, respectively, on the 14th day. These results indicate that AE0047 may be expected to exhibit beneficial effects for the clinical treatment of hypertension.
Asunto(s)
Antihipertensivos/administración & dosificación , Bloqueadores de los Canales de Calcio/administración & dosificación , Cardiomegalia/tratamiento farmacológico , Dihidropiridinas/administración & dosificación , Hipertensión/tratamiento farmacológico , Animales , Presión Sanguínea/efectos de los fármacos , Perros , Frecuencia Cardíaca/efectos de los fármacos , Hipertensión Renal/tratamiento farmacológico , Masculino , Ratas , Ratas Endogámicas SHRRESUMEN
Antihypertensive drugs are expected to have a lipid-lowering effect for use in treating ischemic heart disease. We evaluated the effect of (+)-N-(6-amino-3-pyridil)-N'-[(1S,2R,4R)-bicyclo-[2.2.1]hept-2-yl] -N"- cyanoguanidine hydrochloride (AL0671), a newly synthesized cyanoguanidine-derivative potassium channel opener, on serum lipid and lipoprotein levels in obese Zucker rats, a genetically engineered model of type IV hyperlipidemia. AL0671 dose-dependently decreased systolic blood pressure in obese Zucker rats. Serial administration (for 1 or 2 weeks) of AL0671 (5 mg/kg/day) significantly decreased serum total triglyceride, chylomicron and very-low-density lipoprotein levels with increasing high-density lipoprotein cholesterol, whereas low-density lipoprotein levels did not change. AL0671 (5 mg/kg/day) increased lipoprotein lipase activities 4-fold and hepatic triglyceride lipase activities 3-fold in postheparin plasma. Another urea-derivative compound, AL0674, whose potassium channel-opening activity is diminished, did not affect serum lipid and lipoprotein levels. These results suggested that AL0671 activates both lipoprotein lipase and hepatic triglyceride lipase activities through its potassium channel-opening activity followed by decreasing triglyceride-rich lipoproteins in genetically obese hyperlipemic rats. Therefore, AL0671 might be beneficial in the treatment of hypertensive patients with hypertriglyceridemia (probably with insulin resistance).
Asunto(s)
Compuestos Bicíclicos con Puentes/farmacología , Guanidinas/farmacología , Hipolipemiantes/farmacología , Metabolismo de los Lípidos , Canales de Potasio/efectos de los fármacos , Animales , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Lipasa/sangre , Lipoproteína Lipasa/sangre , Prazosina/farmacología , Ratas , Ratas Zucker , Receptores de LDL/efectos de los fármacosRESUMEN
This report describes the synthesis and pharmacological evaluation of a series of novel potassium channel openers related to the pinacidil-type compounds. Thioureas, cyanoguanidines, and pyridine N-oxides were systematically evaluated for their effects on both the inhibition of spontaneous mechanical activity in rat portal vein (in vitro) and their antihypertensive activity (in vivo), and the structure-activity relationship for this series of compounds was discussed. Good correlation between in vitro and iv antihypertensive activity was observed for these compounds. Among them, cyanoguanidines bearing a conformationally rigid unit such as a norbornyl group generally possessed potent activity in both in vitro and in vivo studies. Especially, N-(6-amino-3-pyridyl)-N'-cyano-N"-(1-methyl-2-norbornyl)guanidine (23d) was identified as a more potent potassium channel opener in vitro (EC100 = 3 x 10(-8) M) than pinacidil (EC100 = 10(-7) M).
Asunto(s)
Antihipertensivos/síntesis química , Guanidinas/química , Guanidinas/farmacología , Norbornanos/química , Norbornanos/farmacología , Canales de Potasio/efectos de los fármacos , 4-Aminopiridina/análogos & derivados , 4-Aminopiridina/química , 4-Aminopiridina/farmacología , Amifampridina , Animales , Antihipertensivos/uso terapéutico , Fenómenos Biomecánicos , Gliburida/farmacología , Hipertensión/tratamiento farmacológico , Masculino , Estructura Molecular , Pinacidilo , Vena Porta/efectos de los fármacos , Vena Porta/fisiología , Ratas , Ratas Endogámicas SHR , Ratas Wistar , Relación Estructura-ActividadRESUMEN
To predict the clinical effect on leukemic disease of a combination regimen developed to circumvent multidrug resistance (MDR), we tested various antitumor agents in the presence and absence of AHC-52, a sensitizing agent for multidrug-resistant cells, in the i.v.-i.v. model of murine leukemia. In this model system, sensitive and resistant P388 murine leukemia cells are inoculated i.v. into mice, and each antitumor agent is injected via the i.v. route. Vincristine (VCR) had no effect on the survival of mice bearing VCR-resistant P388, a relatively poorly resistant subline, when given either as a single agent or in combination with AHC-52. In contrast, adriamycin (ADR) alone had no effect on these mice, but its combination with AHC-52 resulted in significant survival, the maximal value achieved being 196% (treated mice/control animals, T/C). Etoposide (VP-16) strongly enhanced survival, even when used alone, and this effect was markedly potentiated by AHC-52. Combination of any antitumor drug with AHC-52 was ineffective in mice bearing ADR-resistant P388, a highly resistant subline. On the other hand, AHC-52 strongly augmented the therapeutic efficacy of these antitumor agents in mice bearing the sensitive parent P388 leukemia, producing some curative effects. On the basis of these results, the feasibility of this type of combination therapy is discussed.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Dihidropiridinas/farmacología , Leucemia P388/tratamiento farmacológico , Pirazoles/farmacología , Animales , Dihidropiridinas/administración & dosificación , Doxorrubicina/administración & dosificación , Doxorrubicina/uso terapéutico , Resistencia a Medicamentos , Sinergismo Farmacológico , Etopósido/administración & dosificación , Etopósido/uso terapéutico , Femenino , Leucemia P388/genética , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos DBA , Pirazoles/administración & dosificación , Vincristina/administración & dosificación , Vincristina/uso terapéuticoRESUMEN
We found atrial natriuretic peptide (ANP), known as a humoral factor in regulating body fluid volume and blood pressure, in considerable quantities in rat superior cervical sympathetic ganglion (SCG) by radioimmunoassay after separation with reverse-phase HPLC. Although the ANP content of the immature rat 1 week after birth was low, it doubled at 2 weeks and then increased gradually, until it reached the adult level. Denervation caused a rapid decrease in the ANP content to half of the intact SCG level after 3 h, which then fell to 10% of the control value on day 2 after operation. The time course of ANP content reduction after denervation was similar but rather faster than that of activity of the acetylcholine-synthesizing enzyme, choline acetyltransferase, an observation suggesting that ANP may partly contribute to cholinergic synaptic transmission. On the other hand, axotomy produced a rather slower decrease in the ANP content than did denervation. Enucleation and sialoadenectomy also caused a considerable reduction of the ANP content. Thus, part of the ANP found in the ganglion is apparently transported from sympathetically innervated extraganglionic organs via retrograde axoplasmic flow.